Methods for coating substrates for pharmaceutical uses with a mixture of two film-forming coating agents

ABSTRACT

The invention relates to methods for producing pharmaceuticals or parts of pharmaceuticals or food supplements or parts thereof, by coating substrates with a mixture of two film-forming coating agents that can contain other pharmaceutically standard additives, especially softeners and/or a pharmaceutical active ingredient.

The invention relates to a method for coating substrates forpharmaceutical uses with a mixture of two film-forming coating agents.

1. Prior art

Abletshauser C. B., describes in “Film coating of pellets with insolublepolymers obtained in situ crosslinking in fluidized bed” in Journal ofControlled Release 27 (1993), pp. 149-156, a method in which afilm-forming polymer, sodium alginate, in aqueous solution and acrosslinker, e.g. a CaCl₂ solution or a (meth)acrylate copolymer withtertiary amino group radicals (EUDRAGIT E@), are sprayed simultaneouslyfrom two separate spray nozzles onto active ingredient-containingpellets. The film application can take place for example in a fluidizedbed apparatus with two spray nozzles installed therein. The method hasan approximately equivalent result to sequential application of the twocomponents, but has the advantage of saving time.

WO 00/05307 describes a method for producing a coating agent and binderfor oral or dermal pharmaceutical forms consisting of (a) 35-98% byweight of a copolymer consisting of free-radical polymerized C1 to C4esters of acrylic or methacrylic acid and further (meth)-acrylatemonomers which have functional tertiary ammonium groups, and (b) 1-50%by weight of a plasticizer, and 1-15% by weight of an emulsifier with anHLB of at least 14, where components (a), (b) and (c) are mixed togetherwith or without addition of water and, where appropriate, with additionof an active pharmaceutical ingredient and further conventionaladditives, and the coating agent and binder is produced by melting,casting, spreading or spraying, where the copolymer (a) is introduced inpowder form with an average particle size of 1-40 μm.

EP-A 0 848 960 describes an adhesive and binder for dermal ortransdermal therapeutic systems consisting of (a1) 55-99.9% by weight ofa (meth)acrylate copolymer of structural and functional monomers, wherethe functional monomers have tertiary or quaternary amino groups, (a2)0.1-45% by weight of an acidic group-containing acrylate or(meth)acrylate polymer or copolymer and (b) 25-80% by weight, based onthe total of (a1) and (a2), of a plasticizer. A transdermal therapeuticsystem can be produced by incorporating an active pharmaceuticalingredient by coating or by spraying or painting of solutions,dispersions, suspensions or melts of an adhesive and binder andsubsequently drying or cooling.

U.S. Pat. No. 6,368,629 describes pH-dependent colonic release systemswhich comprise a core, an inner polymer coating, e.g. a mixture ofEUDRAGIT® E and EUDRAGIT® RS, and have an outer coating of a polymerwith anionic groups, e.g. a EUDRAGIT® L.

Problem and Solution

It is possible by means of the mixture, described in EP-A 0 848 960, oftwo (meth)acrylate copolymers to produce transdermal therapeutic systemswith advantageous properties in relation to active ingredient release.It would be desirable to be able to apply this release system also tocoating agents for pharmaceutical substrates such as, for example,active ingredient-containing tablet cores.

This is in principle possible without difficulty if organic solutions ofthe two ingredients are mixed and used for spray applications. Thedisadvantage of this procedure is the use of organic solvents which areknown to involve problems in safety at work and in environmentalprotection.

If aqueous dispersions, instead of organic solutions, of the(meth)acrylate copolymers are chosen as initial basis, the difficultyarises that mixtures of the two (meth)acrylate copolymers showincompatible behavior and remain sprayable for only a short time. Thismeans that mixed dispersions become unstable and are prone toaggregation or coagulation after only a short time. Since even slightaggregate formation lead to blockage of spray nozzles, such mixturecannot at present be employed industrially in an acceptable manner.

It is true that said aggregate formation can be avoided in aqueoussystems by adding comparatively large amounts, 10% by weight or more, ofnonionic emulsifiers. However, this is problematic because the aim inpharmaceutical applications is to keep the use of emulsifiers at a lowlevel. The presence of large amounts of these substances frequentlyleads to problems with the long-term stability of the producedpharmaceutical forms. Thus, unwanted interactions with the activeingredient may occur during storage. Manifestation of inhomogeneity inthe polymer coatings are also possible. Both these are undesired and, ofcourse, unacceptable for pharmaceuticals.

The problem was therefore regarded as being to make (meth)acrylatecopolymer mixtures like those described in EP-A 0 848 960 fortransdermal systems also available for aqueous spray applicationsystems. It is moreover intended that the use of nonionic emulsifierseither be completely avoidable or take place only in small amounts. Theresulting coatings are intended to be of satisfactory quality, non-tackyand have long-term stability.

The problem is solved by a

method for producing pharmaceutical forms or parts of pharmaceuticalforms or food supplements or parts thereof,

by coating substrates with a mixture of two film-forming coating agentswhich may comprise further pharmaceutically customary additives,especially plasticizers and/or an active pharmaceutical ingredient,

where the first film-forming coating agent

is a (meth)acrylate copolymer of 30 to 80% by weight free-radicalpolymerized C₁ to C₄ alkyl esters of acrylic or methacrylic acid and 70to 20% by weight (meth)acrylate monomers having a tertiary amino groupin the alkyl radical,

and the second film-forming coating agent is a polymer having anionicgroups,

with the proviso that the film-forming coating agents comprise, based onthe dry matter of the mixture, no or not more than 20% by weight of aplasticizer and no or not more than 5% by weight of a nonionicemulsifier,

-   -   characterized in that

the film-forming coating agents are initially separate from one anotherin the form of liquid, sprayable solutions or dispersions, and

are simultaneously sprayed by spray application using one or more spraydevices which, singly or together, atomize liquids separately, and whosespray beams overlap,

in such a way that the incompatible individual portions are mixed in thespraying process, the mixture impinges on the substrate and formsthereon, after evaporation of the water, a film coating, resulting inthe pharmaceutical form food supplement or parts thereof.

The simultaneous spraying according to the invention of the otherwisemutually incompatible components and the mixing thereof in the spraybeam makes it possible to use the polymer mixture for spray application.A further advantage of this procedure is inter alia that additives suchas plasticizers or nonionic emulsifiers can be kept at low levels interms of amount or be entirely avoided.

Implementation of the Invention

The invention relates to a method for producing pharmaceutical forms orparts of pharmaceutical forms or food supplements or parts thereof, bycoating substrates with a mixture of two film-forming coating agentswhich may comprise further pharmaceutically customary additives,especially plasticizers and/or an active pharmaceutical ingredient,

where the first film-forming coating agent is a (meth)acrylate copolymerof 30 to 80% by weight free-radical polymerized C₁ to C₄ alkyl esters ofacrylic or methacrylic acid and 70 to 20% by weight (meth)acrylatemonomers having a tertiary amino group in the alkyl radical,

and the second film-forming coating agent is a polymer having anionicgroups,

with the proviso that the film-forming coating agents comprise, based onthe dry matter of the mixture, no or not more than 20% by weight of aplasticizer and no or not more than 5% by weight of a nonionicemulsifier,

-   -   characterized in that

the film-forming coating agents are initially separate from one anotherin the form of liquid, sprayable solutions or dispersions, and

are simultaneously sprayed by spray application using one or more spraydevices which, singly or together, have at least two separate nozzlesfor liquids, and whose spray beams overlap,

in such a way that the incompatible individual portions are mixed in thespraying process, the mixture impinges on the substrate and formsthereon, after evaporation of the water, a film coating, resulting inthe pharmaceutical form food supplement or parts thereof.

The Film-Forming Coating Agents

The film-forming coating agents are in the form of solutions orsprayable dispersions. Each of the two coating agents may be in one orthe other form. The dispersions may comprise for example a solidscontent of from 10 to 60, preferably 20 to 40, % by weight(meth)acrylate copolymer. The (meth)acrylate copolymers are present inthe water in a fine dispersion in the form of particles with particlesizes in the range from, for example, 5 nm to 30 μm, preferably 10 nm to500 nm. The dispersions are each stable as such. On removal of water bydrying after the spraying, the particles combine and result incontinuous (meth)acrylate copolymer coatings on the particularsubstrate.

Conventional pharmaceutical excipients may additionally be present, butwith the proviso that the film-forming coating agents comprise, based onthe dry matter of the mixture, no or not more than 20% by weight of aplasticizer and no or not more than 5% by weight of a nonionicemulsifier.

The film-forming coating agents (dispersions) comprise, in total, basedon the dry matter of the mixture, no or not more than 20% by weight of aplasticizer and no or not more than 5% by weight of a nonionicemulsifier.

The First Film-Forming Coating Agent

The (meth)acrylate copolymer is composed of 30 to 80% by weight offree-radical polymerized C₁ to C₄ alkyl esters of acrylic or methacrylicacid and 70 to 20% by weight of (meth)acrylate monomers with a tertiaryamino group in the alkyl radical.

Suitable monomers with functional tertiary amino groups are listed inU.S. Pat. No. 4,705,695, column 3, line 64 to column 4, line 13.Particular mention should be made of dimethylaminoethyl acrylate,2-dimethylaminopropyl acrylate, dimethylaminopropyl methacrylate,dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate,(3-dimethylamino-2,2-dimethyl)propyl acrylate,dimethylamino-2,2-dimethyl)propyl methacrylate,(3-diethylamino-2,2-dimethyl)propyl acrylate anddiethylamino-2,2-dimethyl)propyl methacrylate. Dimethylaminoethylmethacrylate is particularly preferred.

The content of monomers with tertiary amino groups in the copolymer canadvantageously be between 20 and 70% by weight, preferably between 40and 60% by weight. The proportions of C₁ to C₄ alkyl esters of acrylicor methacrylic acid is 70-30% by weight. Mention should be made ofmethyl methacrylate, ethyl methacrylate, butyl methacrylate, methylacrylate, ethyl acrylate and butyl acrylate.

A suitable (meth)acrylate copolymer with tertiary amino groups may becomposed for example of 20-30% by weight methyl methacrylate, 20-30% byweight butyl methacrylate and 60-40% by weight dimethylaminoethylmethacrylate.

A specifically suitable commercially available (meth)acrylate copolymerwith tertiary amino groups is composed for example of 25% by weightmethyl methacrylate, 25% by weight butyl methacrylate and 50% by weightdimethylaminoethyl methacrylate (EUDRAGIT® E100).

The (meth)acrylate copolymer can be obtained in a manner known per se byfree-radical bulk, solution, bead or emulsion polymerization. It maybefore processing be brought to the suitable particle size range bysuitable grinding, drying or spraying processes.

Suitable apparatuses for producing powders are familiar to the skilledworker, e.g. air jet mills, pinned disk mills, compartment mills. It ispossible where appropriate to include appropriate sieving steps. Asuitable mill for industrial large quantities is, for example, anopposed jet mill (Multi No. 4200) which is operated with a gage pressureof about 6 bar.

The average particle size of the powders can be determined as follows:

By air jet sieving to divide up the ground product easily into a fewfractions. This method is somewhat less exact than the alternatives inthis range of measurement.

A further very suitable measurement method is laser diffraction todetermine the particle size distribution. Commercially availableapparatuses permit measurement in air (Malvern S3.01 particle sizer) orpreferably in liquid media (LOT, Galai CIS 1). A precondition formeasurement in liquids is that the polymer does not dissolve therein orthe particles change in another way during the measurement. A suitablemedium is, for example, a highly dilute (approx. 0.02% strength) aqueouspolysorbate 80 solution.

At least 70, preferably 90, % of the particles based on the mass (massdistribution) can preferably be in the 1-40 μm size range.

(Meth)acrylate copolymers with an average particle diameter must be inthe range between 1 and 40, preferably between 5 and 35, in particularbetween 10 and 20, μm are preferred. (EUDRAGIT® EPO type).

The Second Film-Forming Coating Agent

The second film-forming coating agent is a polymer having anionic groupsand may be a cellulose derivative, e.g. cellulose acetate phthalate(CAP), cellulose acetate succinate (CAS), cellulose acetate trimelitate(CAT), hydroxypropylmethylcellulose phthalate (HPMCP), a polyvinylacetate derivative, e.g. polyvinyl acetate phthalate, (PVAP) or a(meth)acrylate copolymer.

The second film-forming coating agent is preferably a (meth)acrylatecopolymer of 40 to 95% by weight free-radical polymerized C₁ to C₄ alkylesters of acrylic or methacrylic acid and comprises 5 to 60% by weight(meth)acrylate monomers having an anionic group in the alkyl radical.

The (meth)acrylate copolymer consists of 40 to 100, preferably 45 to 99,in particular 85 to 95, % by weight of free-radical polymerized C₁ to C₄alkyl esters of acrylic or methacrylic acid and may comprise 0 to 60,preferably 1 to 55, in particular 5 to 15, % by weight of (meth)acrylatemonomers having an anionic group in the alkyl radical.

Normally, the proportions mentioned add up to 100% by weight. However,small amounts in the range from 0 to 10, e.g. 1 to 5, % by weight offurther vinylically copolymerizable monomers such as, for example,hydroxyethyl methacrylate or hydroxyethyl acrylate may additionally bepresent without this leading to an impairment or alteration of theessential properties.

C₁ to C₄ alkyl esters of acrylic or methacrylic acid are in particularmethyl methacrylate, ethyl methacrylate, butyl methacrylate, methylacrylate, ethyl acrylate and butyl acrylate.

A (meth)acrylate monomer having an anionic group in the alkyl radicalmay be for example acrylic acid, but preferably methacrylic acid.

Also suitable are anionic (meth)acrylate copolymers composed of 40 to60% by weight methacrylic acid and 60 to 40% by weight methylmethacrylate or 60 to 40% by weight ethyl acrylate (EUDRAGIT® L orEUDRAGIT® L100-55 types).

EUDRAGIT® L100-55 is a copolymer of 50% by weight ethyl acrylate and 50%by weight methacrylic acid. EUDRAGIT® L30-55 is a dispersion comprising30% by weight EUDRAGIT® L 100-55.

Likewise suitable are anionic (meth)acrylate copolymers of 20 to 40% byweight methacrylic acid and 80 to 60% by weight methyl methacrylate(EUDRAGIT® S type).

(Meth)acrylate copolymers consisting of 10 to 30% by weight methylmethacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weightmethacrylic acid (EUDRAGIT® FS type) are particularly well suited.EUDRAGIT® FS is a copolymer of 25% by weight methyl methacrylate, 65% byweight methyl acrylate and 10% by weight methacrylic acid. EUDRAGIT® FS30 D is a dispersion comprising 30% by weight EUDRAGIT® FS.

The copolymers are obtained in a manner known per se by free-radicalbulk, solution, bead or emulsion polymerization. They must beforeprocessing be brought to the particle size range of the invention bysuitable grinding, drying or spraying processes. This can take place bysimple crushing of extruded and cooled pellets or hot cut.

The use of powders may be advantageous especially on mixture with otherpowders or liquids. Suitable apparatuses for producing powders arefamiliar to the skilled worker, e.g. air jet mills, pinned disk mills,compartment mills. It is possible where appropriate to includeappropriate sieving steps. A suitable mill for industrial largequantities is, for example, an opposed jet mill (Multi No. 4200) whichis operated with a gage pressure of about 6 bar.

The film-forming polymers are in each case in the form of a solution oraqueous disperse system which permits film formation under the usualconditions of pharmaceutical coating methods.

Further commercially available anionic polymers:

cellulose glycolate (Duodcell®)

cellulose acetate phthalate (CAP, Cellulosi acetas,

PhEur, Cellulose acetate phthalate, NF, Aquateric®)

cellulose acetate succinate (CAS)

cellulose acetate trimeliates (CAT)

hydroxypropylmethylcellulose phthalate (HPMCP, HP 50, HP 55)

polyvinyl acetate phthalate (PVAP)

vinyl acetate-vinylpyrolidone copolymer (PVAc, Kollidon® VA64)

Substrates

The substrates for pharmaceutical applications may be for example activeingredient crystals, active ingredient-containing cores, granules,tablets, pellets or capsules. These may be of regular or irregularshape.

The size of granules, pellets or crystals is between 0.01 and 2.5 mm,that of tablets is between 2.5 and 30.0 mm. Capsules consist for exampleof gelatin, starch or cellulose derivatives.

The substrates may comprise a biologically active substance (activeingredient) up to 95% and further pharmaceutical excipients up to 99.9%by weight.

Usual production processes are direct compression, compression of dry,moist or sintered granules, extrusion and subsequent rounding off, wetor dry granulation or direct pelleting (e.g. on plates) or by binding ofpowders (powder layering) onto active ingredient-free beads(nonpareilles) or active ingredient-containing particles.

Besides the active ingredient, further pharmaceutical excipients may bepresent, such as, for example, binders such as cellulose and derivativesthereof, polyvinylpyrrolidone (PVP), humectants, disintegrationpromoters, lubricants, disintegrants, (meth)acrylates, starch andderivatives thereof, sugar solubilizers or others.

Spray Device

It is possible to employ or use as spray device those having two or moretwo-fluid nozzles or one or more three-fluid nozzles.

In a two-fluid nozzle or a three-fluid nozzle, in each case one of thenozzle orifices is supplied with compressed air to atomize the liquidwhich is sprayed at the same time. The other or the two other spraynozzles serve to eject the respective film-forming coating agent. Tocarry out the method, therefore, either at least two two-fluid nozzlesare required, where one in each case sprays the first film-formingcoating agent and the liquid with the further substance, or athree-fluid nozzle, which sprays both simultaneously, is required.

The delivery rates of the sprayed liquids can be influencedindependently of one another by the setting of parameters such as, forexample, the pump outputs or the spraying pressure and/or the airdelivery rates. It is possible in principle for the settings of thespray devices to be carried out manually during the spraying process. Inorder to obtain reproducible results, it is preferred to control theparameters which influence the delivery rates of the sprayed liquids bymeans of fixed programs, e.g. by electronic means.

Examples of commercially available spray devices are, for example, thePilot SIL XII spray gun (double two-fluid nozzle; manufactured byWalther, Wuppertal, Germany), the “Concentric Dual-Feed Nozzle” model(three-fluid nozzle, manufactured by ShinEtsu, Japan) or model 946-S15(three-fluid nozzle, manufactured by Dusen Schlick GmbH, D-96253Untersiemau, Germany).

Spray Application

Spray application takes place by means of one or more spray deviceswhich have, singly or together, at least two separate nozzles forliquids and whose spray beams overlap.

The two film-forming coating agents are initially separate from oneanother in the form of sprayable dispersions and are sprayedsimultaneously in such a way that the incompatible individual portionsmix during the spraying, impinge on the substrate and thereon, afterevaporation of the water content, a uniform film coating.

The spray solutions are fed to the nozzles through tubing by means ofpumps which generate low shear forces. Tubing pumps are preferred.

In order to ensure good mixing, the simultaneous spraying preferablytakes place with a respective spraying pressure in the range from 0.8 to1.5 bar.

The film-forming coating agents are preferably employed in a mixingratio of from 9:1 to 1:9 based on the total polymer mass of the filmcoating.

The spray application can take place for example in a drum coater, acoating pan, a fluidized bed apparatus or a spray sifter.

The spray application can take place using manually guided spraydevices. However, better and more reproducible results are usuallyobtained with spray devices which are fixed installations, so that theseare preferred.

Equipment

The method is particularly preferably carried out with drum coaters,coating pans, fluidized bed apparatuses or spray sifters comprising asspray device one or more three-fluid nozzles, in particular as fixedinstallation.

Coated Pharmaceutical Form or Coated Food Supplement

Coated pharmaceutical forms or parts of pharmaceutical forms or foodsupplements or parts thereof can in particular be produced or obtainedby means of the method of the invention. The sprayed individual portionsare mixed together within fractions of seconds during the sprayapplication and, through the evaporation of the water which proceedsvirtually simultaneously, form a polymer matrix on the surface of thesubstrates. The resulting molecular matrix structure should thereforediffer from a matrix structure produced when both film-forming coatingagents is present in a polymer dispersion before the spraying. Despitethis difference, no adverse effects compared with conventional methodsare found in the quality of the coating, e.g. gloss or uniformity; onthe contrary, novel properties differing from the initial polymers areobtained. It is surprising that slow-release pharmaceutical forms whichhave pH-independent release and display partially sigmoidal releaseprofiles are obtained.

The applied amount of polymer depends on the shape and size of thesubstrate. A complete coating is always necessary for reliable controlof release. This amount amount of polymer is above 1% by weight fortablets and above 5% by weight for granules, powders or pellets, in eachcase based on the uncoated substrate.

The air pressure generating the spray mist is between 0.5 and 3 bar,preferably between 1 and 2 bar. Only in rare cases where the viscosityof one or both spray liquids is distinctly higher than water may it benecessary to increase the spraying pressure further.

The spraying rate of the two individual components may differ anddepends greatly on the batch size, the individual formula and the dryingcapacity, determined by the air throughput, of the equipment used.Ordinarily, the total of the spraying rates of the two liquids is 1 to15 g/kg of cores×min, preferably 5 to 10 g/kg of cores×min).

The product temperature to be maintained during the spraying depends onthe formula of the individual components used and the properties,determined thereby, of the film former. Guideline values are from 15 to50° C., preferably 20 to 40° C., particularly preferably 25 to 35° C.

It is also possible where appropriate to apply a rapidly releasedinitial dose. The active ingredient is in this case incorporated into awater-soluble binder.

The pharmaceutical form may comprise an active ingredient from the classof analgesics, antiallergics, antiarrhythmics, antibiotics,chemotherapeutics, antidiabetics, antidotes, antiepileptics,antihypertensives, antihypotensives, anticoagulants, antimycotics,antiinflammatory agents, beta-receptor blockers, calcium antagonists andACE inhibitors, bronchospasmolytics/antiasthmatics, cholinergics,corticoids (for internal use), diuretics, enzyme inhibitors, enzymepreparations and transport proteins, expectorants, geriatrics, goutremedies, influenza remedies, hormones and their inhibitors,hypnotics/sedatives, cardiac drugs, lipid-lowering agents, parathyroidhormones/calcium metabolism regulators, psychoactive drugs, sex hormonesand their inhibitors, spasmolytics, sympatholytics, sympathomimetics,vitamins, wound-treatment agents, cytostatics, nucleic acids, proteinsor peptides.

Medicinal substances in use can be found in reference works such as, forexample, the Rote Liste or the Merck Index.

Biologically Active Substances:

The medicinal substances employed for the purposes of the invention areintended to be used on or in the human or animal body in order,

-   -   1. to cure, to alleviate, to prevent or to diagnose disorders,        conditions, physical damage or pathological symptoms.    -   2. to reveal the condition, the status or the functions of the        body or mental states.    -   3. to replace active substances or body fluids produced by the        human or animal body.    -   4. to ward off, to eliminate or to render harmless pathogens,        parasites or exogenous substances, or    -   5. to influence the condition, the status or the functions of        the body or mental states.

The formulation of the invention is suitable for administration of inprinciple any active pharmaceutical ingredients or biologically activesubstances which can preferably be administered in slow-release form.

These pharmaceutically active substances may belong to one or moreactive ingredient classes such as ACE inhibitors, adrenergics,adrenocorticosteroids, acne therapeutic agents, aldose reductaseinhibitors, aldosterone antagonists, alpha-glucosidase inhibitors, alpha1 antagonists, remedies for alcohol abuse, amino acids, amebicides,anabolics, analeptics, anesthetic additions, anesthetics(non-inhalational), anesthetics (local), analgesics, androgens, anginatherapeutic agents, antagonists, antiallergics, antiallergics such asPDE inhibitors, antiallergics for asthma treatment, furtherantiallergics (e.g. leukotriene antagonists, antianemics, antiandrogens,antianxiolytics, antiarthritics, antiarrhythmics, antiatheriosclerotics,antibiotics, anticholinergics, anticonvulsants, anti-depressants,antidiabetics, antidiarrheals, antidiuretics, antidotes, antiemetics,antiepileptics, antifibrinolytics, antiepileptics, antihelmintics,antihistamines, antihypotensives, antihypertensives, antihypertensives,antihypotensives, anticoagulants, antimycotics, antiestrogens,antiestrogens (non-steroidal), antiparkinson agents, antiinflammatoryagents, antiproliferative active ingredients, antiprotozoal activeingredients, antirheumatics, antischistosomicides, antispasmolytics,antithrombotics, antitussives, appetite suppressants, arteriosclerosisremedies, bacteriostatics, beta-blockers, beta-receptor blockers,bronchodilators, carbonic anhydrase inhibitors, chemotherapeutic agents,choleretics, cholinergics, cholinergic agonists, cholinesteraseinhibitors, agents for the treatment of ulcerative colitis, diuretics,ectoparasiticides, emetics, enzymes, enzyme inhibitors, enzymeinhibitors, active ingredients to counter vomiting, fibrinolytics,fungistatics, gout remedies, glaucoma therapeutic agents,glucocorticoids, glucocorticosteroids, hemostatics, cardiac glycosides,histamine H2 antagonists, hormones and their inhibitors,immunotherapeutic agents, cardiotonics, coccidiostats, laxatives,lipid-lowering agents, gastrointestinal therapeutic agents, malariatherapeutic agents, migraine remedies, microbiocides, Crohn's disease,metastasis inhibitors, migraine remedies, mineral preparations,motility-increasing active ingredients, muscle relaxants, neuroleptics,active ingredients for treatment of estrogens, osteoporosis,otologicals, antiparkinson agents, phytopharmaceuticals, proton pumpinhibitors, prostaglandins, active ingredients for treating benignprostate hyperblasia, active ingredients for treating pruritus,psoriasis active ingredients, psychoactive drugs, radical scavengers,renin antagonists, thyroid therapeutic agents, active ingredients fortreating seborrhea, active ingredients to counter seasickness,spasmolytics, alpha- and beta-sympathomimetics, platelet aggregationinhibitors, tranquilizers, ulcer therapeutic agents, further ulcertherapeutic agents, agents for the treatment of urolithiasis,virustatics, virustatics, vitamins, cytokines, active ingredients forcombination therapy with cytostatics, cytostatics.

Examples of suitable active ingredients are acarbose, acetylsalicylicacid, aclarubicin, acyclovir, cisplatin, actinomycin,adenosylmethionine, adrenaline and adrenaline derivatives, alemtuzumab,allopurinol, almotriptan, alosetron, alprostadil, amantadine, ambroxol,amlodipine, amoxicillin, 5-aminosalicylic acid, amitriptyline,amlodipine, amoxicillin, anastrozole, androgen and androgen derivatives,atenolol, atorvastatin, azathioprine, azelaic acid, barbituric acidderivatives, balsalazide, beclomethasone, benzodiazepines, betahistine,bezafibrate, bicalutamide, bimatoprost, budesonide, bufexamac,buprenorphine, bupropion, butizine, calcium antagonists, calcium salts,candesartan, capecitabine, captopril, carbamazepine, caspofungin,cefadroxil, cefalosporins, cefditoren, cefprozil, celetoxib, cetirizine,chenodeoxycholic acid, ciclosporin, cimetidine, clarithromycin,clavulanic acid, clindamycin, clobutinol, clonidine, codeine, caffeine,colestyramine, cromoglicic acid, cotrimoxazole, coumarin and coumarinderivatives, cysteine, cytarabine, cyclophosphamide, cyproterone,cytarabine, dapiprazole, desipramine, desogestrel, desonide, disoproxil,diazepam and diazepam derivatives, dihydralazine, diltiazem,dimenhydrinate, dimethyl sulfoxide, dimeticone, dipyridarnoi,domperidone, and domperidane derivatives, donepzil, dopamine, doxazosin,doxorubizin, doxylamine, diclofenac, divalproex, drospirenone,econazole, emtricitabine, enalapril, ephedrine, epinephrine, epoetin andepoetin derivatives, eprosartan, esomeprazole, estrogen and estrogenderivatives, ethenzamide, ethinestradiol, etofenamate, etofibrate,etofylline, etonorgestrel, etoposide, famciclovir, famotidine,felodipine, fenofibrate, fentanyl, fenticonazole, fexofenadine,fluconazole, fludarabine, flunarizine, fluorouracil, fluoxetine,flurbiprofen, flupirtine, flutamide, fluvastatin, follitropin,formoterol, fosfomicin, frovatriptan, furosemide, fusidic acid,galantamine, gallopamil, ganciclovir, gemfibrozil, gentamicin,progestogen and progestogen derivatives, ginkgo, glibenclamide,glucagon, glucitol and glucitol derivatives, glucosamine and glucosaminederivatives, glycoside antibiotics, urea derivatives as oralantidiabetics, glutathione, glycerol and glycerol derivatives,hypothalamus hormones, goserelin, gyrase inhibitors, guanethidine,gyrase inhibitors, halofantrine, haloperidol, heparin and heparinderivatives, cardiac glycosides, hyaluronic acid, hydralazine,hydrochlorothiazide and hydrochlorothiazide derivatives,hydroxyomeprazole, hydroxyzine, ibuprofen, idarubicin, ifosfamide,imatinib, imipramine, indometacin, indoramine, insulin, interferons,irinotecan, isoconazole, isoprenaline, itraconazole, ivabradines, iodineand iodine derivatives, St. John's wort, potassium salts, ketoconazole,ketoprofen, ketotifen, lacidipine, lansoprazole, letrozol, levodopa,levomethadone, lipoic acid and lipoic acid derivatives, lisinopril,lisuride, lofepramine, lomustine, loperamide, loratadine, magnesiumsalts, macrolide antibiotics, maprotiline, mebehdazole, mebeverine,meclozine, mefenamic acid, mefloquine, meloxicam, mepindolol,meprobamate, meropenem, mesalazine, mesuximide, metamizole, metformin,methadone, methotrexate, methylnaloxone, methylnaltrexones,methylphenidate, methylprednisolone, metixen, metoclopramide,metoprolol, metronidazole, mianserin, miconazole, minocycline,minoxidil, misoprostol, mitomycin, mizolastine, modafinil, moexipril,morphinans, morphine and morphine derivatives, ergot alkaloids,nalbuphine, naloxone, naproxen, narcotine, natamycin, neostigmine,neramexan, nicergoline, nicethamide, nifedipine, niflumic acid,nimodipine, nimorazole, nimustine, nesiritide, nisoldipine, norfloxacin,novamine sulfone, noscapine, nystatin, ofloxacin, olanzapine,olsalazine, omeprazole, omoconazole, ondansetron, orlistat, oseltamivir,oxaceprol, oxacillin, oxiconazole, oxymetazoline, pantoprazole,paracetamol, paroxetine, peginterferon, penciclovir, oral penicillins,pentazocine, pentifylline, pentoxifylline, peptide antibiotics,perindopril, perphenazine, pethidine, plant extracts, phenazone,pheniramine, phenytoin, phenothiazines, phenylbutazone, phenytoin,pimozide, pindolol, piperazine, piracetam, pirenzepine, piribedil,piroxicam, pramipexol, pravastatin, prazosin, procaine, promazine,propiverine, propranolol, propyphenazone, prostaglandins, protionamide,proxyphylline, quetiapine, quinapril, quinaprilate, ramipril,ranitidine, ranolazines, reproterol, reserpine, ribavirin, rifampicin,riluzoles, risedronate, risperidone, ritonavir, ropinirol,rosiglitazone, roxatidine, roxithromycin, ruscogenin, rosuvastatin,rutoside and rutoside derivatives, sabadilla, salbutamol, salicylates,salmeterol, thyroid hormones, scopolamine, selegiline, sertaconazole,sertindole, sertralion, sildenafil, silicates, simvastatin, sitosterol,sotalol, spaglumic acid, sparfloxacin, spectinomycin, spiramycin,spirapril, spironolactone, stavudine, streptomycin, sucralfate,sufentanil, sulbactam, sulfonamides, sulfasalazine, sulpiride,sultamicillin, sultiam, sumatriptan, suxamethonium chloride, tacrine,tacrolimus, tadalafil, taliolol, talsaclidine, tamoxifen, tazarotene,tegaserod, temazepam, teniposide, tenofovir, tenoxicam, terazosin,terbinafine, terbutaline, terfenadine, terlipressin, tertatoloL,testosterone and testosterone derivatives, tetracyclines, tetryzoline,theobromine, theophylline, theophylline derivatives, trypsins,thiamazole, thiotepa, tiagabine, tiapride, propionic acid derivatives,ticlopidine, tilidine, timolol, tinidazole, tioconazole, tioguanine,tioxolone, tiropramide, tizanidine, tolazoline, tolbutamide, tolcapone,tolnaftate, tolperisone, topiramate, topotecan, torasemide, tramadol,tramazoline, trandolapril, tranylcypromine, trapidil, trazodone,triamcinolone and triamcinolone derivatives, triamterene, trifluperidol,trifluridine, trimetazidines, trimethoprim, trimipramine,tripelennamine, triprolidine, trifosfamide, tromantadine, trometamol,tropalpine, troxerutin, tulobuterol, tyramine, tyrothricin, urapidil,ursodeoxycholic acid, theophylline ursodeoxycholic acid, valaciclovir,valdecoxib, valganciclovir, valproic acid, vancomycin, vardenafil,vecuronium chloride, venlafaxine, verapamil, vidarabine, vigabatrine,viloxazine, vinblastine, vincamine, vincristine, vindesine, vinorelbine,vinpocetine, viquidil, vitamin D and derivatives of vitamin D, warfarin,xantinol nicotinate, xipamide, zafirlukast, zalcitabine, zanamivir,zidovudine, ziprasidone, zoledronic acid, zolmitriptan, zolpidem,zoplicone, zotepine and the like.

The active ingredients can if desired also be used in the form of theirpharmaceutically acceptable salts or derivatives, and in the case ofchiral active ingredients it is possible to employ both optically activeisomers and racemates or mixtures of diastereoisomers. If desired, thecompositions of the invention may also comprise two or more activepharmaceutical ingredients.

The pharmaceutical forms are preferably multi-particulate, for examplein the form of capsules, sachets, powders for reconstitution ordisintegrating tablets.

Excipients Customary in Pharmacy

The film-forming coating agents should comprise, based on the dry matterof the mixture, no or not more than 20% by weight of a plasticizer andno or not more than 5% by weight of a nonionic emulsifier.

Plasticizers: Substances suitable as plasticizers ordinarily have amolecular weight between 100 and 20 000 and contain one or morehydrophilic groups in the molecule, e.g. hydroxyl, ester or aminogroups. Citrates, phthalates, sebacates, castor oil are suitable.Examples of suitable plasticizers are alkyl citrates, propylene glycol,glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters,sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethyleneglycols 4000 to 20 000. Preferred plasticizers are tributyl citrate,triethyl citrate, acetyl triethyl citrate, dibutyl sebacate and diethylsebacate. The amounts used are between 1 and 20, preferably 2 to 10, % %by weight based on the (meth)acrylate copolymer.

Emulsifiers

If emulsifiers are present in the coating agents, they should betoxicologically acceptable. In principle, nonionic emulsifiers arepreferred for pharmaceuticals.

Suitable classes of emulsifiers are ethoxylated fatty acid esters orethers, ethoxylated sorbitan ethers, ethoxylated alkylphenols, glycerolesters or sugar esters or wax derivatives.

Examples of suitable emulsifiers are polyoxyethylene glycerolmonolaurate, polyoxyethylene glycerol monostearate, polyoxyethylene 25cetylstearate, polyoxyethylene 25 oxypropylene monostearate,polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 16tert-octylphenol, polyoxyethylene 20 cetyl ether, polyethylene glycol(1000) monocetyl ether, ethoxylated castor oil, polyoxyethylene sorbitolwool wax derivatives, polyoxyethylene (25) propylene glycol stearate,polyoxyethylene sorbitol esters polyoxyethylene 25 cetylstearate,polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 16tertoctylphenol and polyoxyethylene 20 cetyl ether.

Dryers (non-stick agents): Dryers have the following properties: theyhave large specific surface areas, are chemically inert, arefree-flowing and comprise fine particles. Because of these properties,they can advantageously be dispersed homogeneously in melts and reducethe tack of polymers containing highly polar comonomers as functionalgroups.

Examples of dryers are:

Alumina, magnesium oxide, kaolin, talc, silica (Aerosils), bariumsulfate, carbon black and cellulose.

Release Agents (Mold Release Agents)

Examples of release agents are:

esters of fatty acids or fatty amides, aliphatic, long-chain carboxylicacids, fatty alcohols and esters thereof, montan waxes or paraffin waxesand metal soaps; particular mention should be made of glycerolmonostearate, stearyl alcohol, glycerol behenic acid ester, cetylalcohol, palmitic acid, canauba wax, beeswax etc.

Further excipients: Mention should be made here of, for example,stabilizers, colorants, antioxidants, wetting agents, pigments, glossagents etc. They are used in particular as processing aids and areintended can be to ensure a reliable and reproducible production processand good long-term storage stability. Further excipients customary inpharmacy may be present in amounts of from 0.001% by weight to 30% byweight, preferably 0.1 to 10% by weight, based on the copolymer.

Preferred active ingredients are:

Morphine and its derivatives, tramadol, acetylsalicylic acid,diclofenac, indometacin, lonazolac, ibuprofen, ketoprofen,propyphenazone, naproxen, paracetamol, flurbiprofen, dimetindene,quinidine, metoprolol, propranolol, oxprenolol, pindolol, atenolol,metoprolol, disopyramide, verapamil, diltiazem, gallopamil, nifedipine,nicardipine, nisoldipine, nimodipine, amlodipine, theophylline,salbutamol, terbutaline, ambroxol, aminophylline, cholinetheophyllinate, pyridostigmine, piretanide, furosemide, pentoxyfylline,naftidrofuryl, buflomedil, xantinol nicotinate, bencyclane, allopurinol,norephedrine, clorphenamine isosorbide mononitrate, isosorbidedinitrate, glycerol trinitrate, molsidomine, bezafibrate, fenofibrate,gemfibrozil, cerivastatin, pravastatin, fluvastatin, lovastatin,atorvastatin, simvastatin, xantinol, metoclopramide, amitriptyline,dibenzepine, venlafaxine, thioridazine, oxazepam, lithium,nitrofurantoin, plant dry extract, ascorbic acid and potassium and thepharmaceutically used salts thereof.

EXAMPLES Example 1

1.1 Production of the Cationic Spray Suspension (First Film-FormingCoating Agent):

114.0 g of EUDRAGIT® E PO (copolymer of methyl methacrylate, butylmethacrylate, and dimethylamino-ethyl methacrylate in the ratio 25:25:50with an average particle size of 15 μm), 8.0 g of sodium lauryl sulfate,17.1 g of dibutyl sebacate, 693.2 g of water and magnesium stearate 34.2g are converted into a polymer dispersion by simple stirring at roomtemperature.

Production of the Anionic Spray Dispersion (Second Film-Forming CoatingAgent):

114.0 g of talc are dispersed in 836.0 g of water with a homogenizer(Ultra Turrax) and stirred into 760.0 g of EUDRAGIT® L 30 D-55(copolymer of 50% by weight ethyl acrylate and 50% by weight methacrylicacid).

A three-fluid nozzle, e.g. Walther Pilot SIL XII, with which theEUDRAGIT® E PO dispersion and the EUDRAGIT® L 30 D55 dispersion(suspension) are fed in separately and mixed immediately after thenozzle outlet, can be used to spray the formula described above onto 3kg of tablets (diameter 10 mm) in a conventional coating pan at a tabletbed temperature of about 30-45° C.° C. with a spraying pressure of about1.2 bar within 170 min to give a homogeneous film. Subsequent drying for15 minutes results in smooth and glossy films which do not dissolve inwater.

Example 2

Production of the Cationic Spray Suspension (First Film-Forming CoatingAgent):

114.0 g of EUDRAGIT® E PO, 1.14 g of sodium lauryl sulfate, 17.1 g ofdibutyl sebacate, 651.8 g of water and magnesium stearate 34.2 g areconverted into a polymer dispersion by simple stirring at roomtemperature.

Production of the Anionic Spray Dispersion:

57.0 g of talc and 17.1 g of triethyl citrate are dispersed in 486.4 gof water with a homogenizer (Ultra Turrax) and stirred into 380.0 g ofEUDRAGIT® L 30 D-55.

A three-fluid nozzle, e.g. Walther Pilot SIL XII, with which theEUDRAGIT® E PO dispersion and the EUDRAGIT® L 30 D55 suspension are fedin separately and mixed immediately after the nozzle outlet, can be usedto spray the formula described above onto 3 kg of tablets (diameter 10mm) in a conventional coating pan at a tablet bed temperature of about33-41° C. with a spraying pressure of about 1.2 bar within 117 min togive a homogeneous film. Subsequent drying for 15 minutes results insmooth and glossy films which do not dissolve in water.

Example 3 Release Investigations on Tablets From Example 1

An approximately 300 mg coated quinidine sulfate tablet with 5% activeingredient content is put into a paddle apparatus with 700 ml of 0.1Nhydrochloric acid, 37° C. and 100 rpm, and the release of activeingredient is tested over 2 hours in this medium via a photometricabsorption at the wavelength of 250.0 nm after 10, 20, 30, 60, 90 and120 min. After 120 min in 0.1N HCl, the pH is adjusted to 6.8 with 200ml of 0.2N Na₃PO₄. The release investigation then likewise takes placevia photometric determination at the wavelengths of 234 nm after 135,150, 180, 210, 240, 300 and 360 min. This is followed by homogenizationand standardization of the total active ingredient concentration to thisvalue as 100% value.

Example 4 Release Investigations on Tablets From Example 2

An approximately 300 mg coated quinidine sulfate tablet with 5% activeingredient content is put into a paddle apparatus with 700 ml of 0.1Nhydrochloric acid, 37° C. and 100 rpm, and the release of activeingredient is tested over 2 hours in this medium via a photometricabsorption at the wavelength of 250.0 nm after 10, 20, 30, 60, 90 and120 min. After 120 min in 0.1N HCl, the pH is adjusted to 6.8 with 200ml of 0.2N Na₃PO₄. The release investigation then likewise takes placevia photometric determination at the wavelengths of 234 nm after 135,150, 180, 210, 240, 300 and 360 min. This is followed by homogenizationand standardization of the total active ingredient concentration to thisvalue as 100% value.

Example 5

A film-forming dispersion is produced from 114.0 g of EUDRAGIT® E PO,1.14 g of sodium lauryl sulfate and 651.8 g of water by stirring at roomtemperature.

(Cationic Polymer Dispersion).

A fine-particle suspension is produced from 17.1 g of triethyl citrate,57.0 g of talc and 486.4 g of water at room temperature using ahomogenizer (Ultra Turrax), introduced into 380.0 g of EUDRAGIT® L 30 D55 and mixed by simple stirring (anionic polymer dispersion). The twoliquids are fed via separate tubing pumps to the nozzle heads of amulti-fluid nozzle (e.g. Walther Pilot SIL XII, and atomized so that themists of the dispersions mix immediately after the nozzle outlet. Thecoating process is carried out on 3 kg of placebo tablets (diameter 10mm) in a conventional coating pan (35 cm diameter) while feeding in hotair. The tablet bed temperature is kept at about 33-41° C. The sprayingpressure of both heads was adjusted to about 1.2 bar. The sprayingprocess lasted about 117 min. Subsequent drying for 15 minutes resultsin smooth, glossy pigmented films which do not dissolve in water.

Example 6 Comparative Example

A film-forming dispersion is produced from 114.0 g of EUDRAGIT® E PO,1.14 g of sodium lauryl sulfate and 651.8 g of water by stirring at roomtemperature.

(Cationic Polymer Dispersion).

A fine-particle suspension is produced from 17.1 g of triethyl citrate,57.0 g of talc and 486.4 g water at room temperature using a homogenizer(Ultra Turrax), introduced into 380.0 g of EUDRAGIT® L 30 D 55 and mixedby simple stirring (anionic polymer dispersion). The two suspensions arefed from separate vessels via tubing pumps to a modified two-fluid NBA 1spray gun (from Walther Trowal) so that mixing of the two suspensionstakes place inside the spray gun, i.e. shortly before the sprayingnozzle. Spray application is not possible because of coagulation in thespray gun.

1. A method for producing pharmaceutical forms or parts ofpharmaceutical forms or food supplements or parts thereof, comprisingcoating substrates with a mixture of two film-forming coating agentswhich may comprise further pharmaceutically customary additives,especially plasticizers and/or an active pharmaceutical ingredient,where the first film-forming coating agent is a (meth)acrylate copolymerof 30 to 80% by weight free-radical polymerized C₁ to C₄ alkyl esters ofacrylic or methacrylic acid and 70 to 20% by weight (meth)acrylatemonomers having a tertiary amino group in the alkyl radical, and thesecond film-forming coating agent is a polymer having anionic groups,with the proviso that the film-forming coating agents comprise, based onthe dry matter of the mixture, no or not more than 20% by weight of aplasticizer and no or not more than 5% by weight of a nonionicemulsifier, wherein the film-forming coating agents are initiallyseparate from one another in the form of liquid, sprayable solutions ordispersions, and are simultaneously sprayed by spray application usingone or more spray devices which, singly or together, atomize liquidsseparately, and whose spray beams overlap, in such a way that theincompatible individual portions are mixed in the spraying process, themixture impinges on the substrate and forms thereon, after evaporationof the water, a film coating, resulting in the pharmaceutical form foodsupplement or parts thereof.
 2. The method as claimed in claim 1,wherein the substrates are active ingredient crystals, activeingredient-containing cores, cores coated with an activeingredient-containing binder, tablets, granules, pellets or capsules. 3.The method as claimed in claim 1 wherein the first film-forming coatingagent is a copolymer of 25% by weight methyl methacrylate, 25% by weightbutyl methacrylate and 50% by weight dimethylaminoethyl methacrylate. 4.The method as claimed in claim 1 wherein the second film-forming coatingagent is a polymer having anionic groups which is a cellulosederivative, a polyvinyl acetate derivative or a (meth)acrylatecopolymer.
 5. The method as claimed in claim 1 wherein the film-formingcoating agents are present in a mixing ratio of from 9:1 to 1:9 based onthe total polymer content of the film coating.
 6. The method as claimedin claim 1 wherein two or more two-fluid nozzles or one or morethree-fluid nozzles are employed as spray device.
 7. The method asclaimed in claim 1 wherein the spray application takes place in a drumcoater, a coating pan, a fluidized bed apparatus or a spray sifter. 8.The method as claimed in claim 7, wherein the spray application takesplace by means of spray devices as fixed installation.
 9. Apharmaceutical form, parts of pharmaceutical forms, food supplements orparts thereof produced by a method as claimed in claim
 1. 10. Apharmaceutical form or parts of pharmaceutical forms as claimed in claim9, wherein an active ingredient from the class of analgesics,antiallergics, antiarrhythmics, antibiotics, chemotherapeutics,antidiabetics, antidotes, antiepileptics, antihypertensives,antihypotensives, anticoagulants, antimycotics, antiinflammatory agents,beta-receptor blockers, calcium antagonists and ACE inhibitors,bronchospasmolytics/antiasthmatics, cholinergics, corticoids (forinternal use), diuretics, enzyme inhibitors, enzyme preparations andtransport proteins, expectorants, geriatrics, gout remedies, influenzaremedies, hormones and their inhibitors, hypnotics/sedatives, cardiacdrugs, lipid-lowering agents, parathyroid hormones/calcium metabolismregulators, psychoactive drugs, sex hormones and their inhibitors,spasmolytics, sympatholytics, sympathomimetics, vitamins,wound-treatment agents, cytostatics, nucleic acids, proteins orpeptides, is present.
 11. A pharmaceutical form or parts ofpharmaceutical forms as claimed in claim 9 wherein the pharmaceuticalforms are multiparticulate.
 12. A drum coater, coating pan, fluidizedbed apparatus or spray sifter suitable for carrying out a method asclaimed in claim 1, comprising one or more three-fluid nozzles as spraydevice.
 13. A method as claimed in claim 1 comprising utilizing one ormore spray devices.